Method and Apparatus for Treatment of Hypertension Through Percutaneous Ultrasound Renal Denervation

ABSTRACT

Apparatus and methods for deactivating renal nerves extending along a renal artery of a mammalian subject to treat hypertension and related conditions. An ultrasonic transducer ( 30 ) is inserted into the renal artery ( 10 ) as, for example, by advancing the distal end of a catheter ( 18 ) bearing the transducer into the renal artery. The ultrasonic transducer emits unfocused ultrasound so as to heat tissues throughout a relatively large impact volume ( 11 ) as, for example, at least about 0.5 cm3 encompassing the renal artery to a temperature sufficient to inactivate nerve conduction but insufficient to cause rapid ablation or necrosis of the tissues. The treatment can be performed without locating or focusing on individual renal nerves.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the filing date of U.S.Provisional Patent Application Nos. 61/256,429, filed on Oct. 30, 2009,and 61/292,618, filed on Jan. 6, 2010, the disclosures of which arehereby incorporated herein by reference.

BACKGROUND OF THE INVENTION

Successful treatment of hypertension is important for many reasons. Forexample, successful treatment of hypertension has significant clinicalbenefits in preventing or limiting conditions caused by or exacerbatedby hypertension, such as renal disease, arrhythmias, and congestiveheart failure, to name a few. While drug therapy can be used to treathypertension, it is not always successful. Some people are resistant todrug therapy treatment or experience significant side effects from drugtherapy treatment.

Hypertension can be treated by inactivating conduction of the renalnerves surrounding the renal artery. Sympathetic renal nerve activityplays a significant role in the initiation and maintenance ofhypertension. When the brain perceives increased renal nerve activity,signaling low blood volume or a drop in blood pressure, it compensatesby increasing sympathetic nerve activity to the heart, the liver, andthe kidneys, which results in increased cardiac output; insulinresistance; and most importantly, increased renin production by thekidneys. Renin stimulates the production of angiotension, which causesblood vessels to constrict, resulting in increased blood pressure andstimulates the secretion of aldosterone. Aldosterone causes the kidneysto increase the reabsorption of sodium and water into the blood,increasing blood volume thereby further increasing blood pressure.

It has been established for years that surgically cutting renal nervesresults in a decrease in blood pressure and water retention to normallevels; thereby allowing the patients' heart, liver, and kidneys to alsoreturn to healthier functioning. It has also been shown a disruption ofthe renal nerves has no serious ill effects. However, surgically cuttingthe renal nerves requires a major surgical procedure with risks ofundesirable side effects. It would be desirable to produce the sameresult without major surgery.

In order to explain the difficulties associated with accomplishing thistask without causing other damage, the anatomy of the renal arteries andnerves will be described now. Shown in FIG. 1 is an illustration of therenal nerves 8 that surround the renal artery 10, which is connected tothe kidney 6. The sympathetic renal nerves 8 include both the afferentsensory renal nerves from the kidney 6 to the brain and the efferentsympathetic renal nerves from the brain to the kidney 6. In addition,FIG. 2 shows a cross-section of a renal artery 10. The renal artery wallincludes layers: the intima 3, which includes an inner single layer ofendothelial cells; the media 5, which is in the center of the arterywall; and the adventitia 4, which is the outside layer. Also shown arethe renal nerves 8 that lie within the aventitia 4, on the surface ofthe renal artery 10, and adjacent to the renal artery 10. As can be seenfrom these two figures, the renal nerves 8 surround the renal artery 10.Different individuals have the renal nerves 8 in different locationsaround the renal artery. Thus, the renal nerves may be at differentradial distances R from the central axis A of the renal artery, and alsomay be at different locations around the circumference C of the renalartery. It is not practical to locate the renal nerves by referring toanatomical landmarks. Moreover, it is difficult or impossible to locateindividual renal nerves using common in vivo imaging technology.

The inability to locate and target the renal nerves 8 makes it difficultto disconnect the sympathetic renal activity using non-surgicaltechniques without causing damage to the renal artery 10 or causingother side effects. For example, attempts to apply energy to the renalnerves can cause effects such as stenosis, intimal hyperplasia, andnecrosis. Other side effects can include thrombosis, plateletaggregation, fibrin clots and vasoconstriction. In addition, theinability to target and locate the renal nerves 8 makes it difficult toensure that sympathetic renal nerve activity has been discontinuedenough to achieve an acceptable therapeutic treatment.

U.S. Pat. No. 7,617,005 suggests the use of a radio frequency (“RF”)emitter connected to a catheter, which is inserted in the renal artery.The RF emitter is placed against the intima and the RF energy is emittedto heat the renal nerves to a temperature that reduces the activity ofrenal nerves which happen to lie in the immediate vicinity of theemitter. In order to treat all the renal nerves surrounding the renalarteries, the RF emitter source must be repositioned around the insideof each renal artery multiple times. The emitter may miss some of therenal nerves, leading to an incomplete treatment. Moreover, the RFenergy source must contact the intima to be able to heat the renalnerves, which may cause damage or necrosis to the single layerendothelium and the intima, potentially causing intimal hyperplasia,renal artery stenosis, and renal artery dissection.

The '005 Patent also suggests the use of high-intensity focusedultrasound to deactivate the renal nerves. The described high-intensityfocused ultrasound energy source assertedly emits ultrasound energy in a360° pattern around the axis of the renal artery, and does not need tocontact the intima 3. However, the high-intensity focused ultrasoundsource applies concentrated energy in a thin focal ring surrounding theartery. It is difficult or impossible to align this thin ring with therenal nerves because it is difficult or impossible to visualize andtarget the renal nerves with current technology, and because the renalnerves may lie at different radial distances from the central axis ofthe renal artery. The latter problem is aggravated in patients who haverenal arteries with large variations in shape or thickness. Moreover,the thin focal ring can encompass only a small segment of each renalnerve along the lengthwise direction of the nerves and artery. Sincenerves tend to re-grow, a small treatment zone allows the nerves toreconnect in a shorter period of time.

For many years ultrasound has been used to enhance cell repair,stimulate the growth of bone cells, enhance delivery of drugs tospecific tissues, and to image tissue within the body. In addition,high-intensity focused ultrasound has been used to heat and ablatetumors and tissue within the body. Ablation of tissue has been performednearly exclusively by high-intensity focused ultrasound because theemitted ultrasound energy is focused on a specific location to allowprecise in-depth tissue necrosis without affecting surrounding tissueand intervening structures that the ultrasound energy must pass through.

U.S. Pat. No. 6,117,101, to Diederich, discusses use of highlycollimated ultrasound energy rather than high intensity focusedultrasound for ablating tissue to create a scar ring within thepulmonary vein for blocking the conduction of electrical signals to theheart.

US Patent Publication No. 20100179424 (application Ser. No. 12/684,067),the disclosure of which is incorporated by reference herein, usesunfocused ultrasound for the treatment of mitral valve regurgitation. Inthe '474 Publication, unfocused ultrasound energy is used to heat andshrink the collagen associated with the mitral annulus. This apparatususes an inflatable balloon in order to place the ultrasound transducerinto the correct location, thereby targeting the mitral annulus. In thisapparatus, a part of the balloon contacts the tissue to be heated.

BRIEF SUMMARY OF THE INVENTION

One aspect of the invention provides apparatus for inactivating renalnerve conduction in a human or non-human mammalian subject. Theapparatus according to this aspect of the invention preferably includesan ultrasound transducer adapted for insertion into a renal artery ofthe mammalian subject. The ultrasound transducer desirably is arrangedto transmit unfocused ultrasound energy. The apparatus according to thisaspect of the invention desirably also includes an actuator electricallyconnected to the transducer. The actuator most preferably is adapted tocontrol the ultrasound transducer to transmit unfocused ultrasoundenergy into an impact volume of at least approximately 0.5 cm³,encompassing the renal artery so that the unfocused ultrasound energy isapplied at a therapeutic level sufficient to inactivate conduction ofrenal nerves throughout the impact volume. As discussed further below,such therapeutic level is below the level required for tissue ablation.

The apparatus may further include a catheter with a distal end and aproximal end, the transducer being mounted to the catheter adjacent thedistal end, the catheter and transducer being constructed and arrangedto allow a substantial flow of blood through the renal artery while theultrasound transducer is positioned within the renal artery. Thecatheter may be constructed and arranged to hold the transducer out ofcontact with the wall of the renal artery. The catheter may have anexpansible element such as a balloon, wire basket or the like mountedadjacent the distal end. For example, the transducer may be adapted totransmit the ultrasound energy in a 360° cylindrical pattern surroundinga transducer axis, and the catheter may be constructed and arranged tohold the axis of the transducer generally parallel to the axis of therenal artery.

A further aspect of the invention provides methods for inactivatingrenal nerve conduction in a mammalian subject. A method according tothis aspect of the invention desirably includes the steps of insertingan ultrasound transducer into a renal artery of the subject andactuating the transducer to transmit therapeutically effective unfocusedultrasound energy into an impact volume of at least approximately 0.5cm³ encompassing the renal artery. The ultrasound energy desirably isapplied so that the therapeutically effective unfocused ultrasoundenergy inactivates conduction of all the renal nerves in the impactvolume. For example, the step of actuating the transducer may be so asto maintain the temperature of the renal artery wall below 65° C. whileheating the solid tissues within the impact volume, including the renalnerves in the impact volume, to above 42° C.

Because the impact volume is relatively large, and because the tissuesthroughout the impact volume preferably reach temperatures sufficient toinactivate nerve conduction, the preferred methods according to thisaspect of the invention can be performed successfully withoutdetermining the actual locations of the renal nerves, and withouttargeting or focusing on the renal nerves. The treatment can beperformed without measuring the temperature of tissues. Moreover, thetreatment preferably is performed without causing stenosis of the renalartery, intimal hyperplasia, or other injuries that would requireintervention. The preferred methods and apparatus can inactiverelatively long segments of the renal nerves, so as to reduce thepossibility of nerve recovery which would re-establish conduction alongthe inactivated segments.

Further aspects of the invention provide probes which can be used in themethod and apparatus discussed above, and apparatus incorporating meansfor performing the steps of the methods discussed above.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an anatomical view of a typical renal artery and associatedstructure.

FIG. 2 is a diagrammatic sectional view depicting a portion of a renalartery and nerves.

FIG. 3 is a diagrammatic view depicting components of apparatus inaccordance with one embodiment of the present invention.

FIG. 4 is a fragmentary diagrammatic perspective view depicting aportion of the apparatus shown in FIG. 3.

FIG. 5 is a diagrammatic view depicting a portion of the apparatus ofFIGS. 3 and 4 in conjunction with a renal artery.

FIG. 6 is a functional, block diagrammatic view depicting portions of acomponent used in the apparatus of FIGS. 3 and 4.

FIG. 7 is a flow chart depicting the steps used in a method according toone embodiment of the present invention.

FIG. 8 is a diagrammatic view depicting portions of the apparatus ofFIGS. 3 and 4 during operation in accordance with the method of FIG. 7.

DETAILED DESCRIPTION

Apparatus according to one embodiment of the invention (FIG. 3) includesa sheath 12. The sheath 12 generally may be in the form of an elongatedtube having a proximal end 14, a distal end 16 and a proximal-to-distalaxis 15. As used in this disclosure with reference to elongated elementsfor insertion into the body, the term “distal” refers to the end whichis inserted into the body first, i.e., the leading end duringadvancement of the element into the body, whereas the term “proximal”refers to the opposite end. The sheath 12 may be a steerable sheath.Thus, the sheath may include known elements such as one or more pullwires (not shown) extending between the proximal and distal ends of thesheath and connected to a steering control 17 arranged so that actuationof the steering control by the operator flexes the distal end 16 of thesheath in a direction transverse to the axis 15.

The apparatus also includes a catheter 18 having a proximal end 20, adistal end 22 and a proximal-to-distal axis which, in the conditiondepicted in FIG. 3 is coincident with the proximal-to-distal axis 15 ofthe sheath. The proximal end 20 of the catheter desirably is relativelystiff such that it may transmit torque. Thus, by turning the proximalend 20 of the catheter 18, distal end 22 of the catheter 18 can berotated about the proximal-to-distal axis of the catheter 18.

The distal end 22 of the catheter 18 is preformed so that when thedistal end of the catheter is outside of the sheath 12, the distal endtends to assume a hooked configuration as indicated in broken lines at22′ in FIG. 3. In this condition, rotational motion of the distal end22′ will swing the curved section around the proximal-to-distal axis.Thus, by rotating the proximal end of the catheter 18, the distal end22′ of the catheter 18 can be positioned in any radial direction.

Catheter 18 has a balloon 24 mounted at the distal end 22. In itsinflated condition (FIG. 4), balloon 24 has a partially non-circularprofile in which one part 82 of the balloon is smaller in diameter thanthe renal artery, whereas another part 80 of the balloon 24 isnoncircular in shape. The noncircular part has a major diameter D_(MAJ)equal to or just slightly less than the internal diameter of the renalartery, and has a minor diameter D_(MIN) smaller than the majordiameter.

An ultrasound transducer 30 (FIGS. 3 and 5) is mounted adjacent thedistal end 22 of catheter 18 within balloon 24. Transducer 30, which isdesirably formed from a ceramic piezoelectric material, is of a tubularshape and has an exterior emitting surface 31 in the form of acylindrical surface of revolution about the proximal-to-distal axis 33of the transducer 30. The transducer 30 typically has an axial lengthalong axis 31 of approximately 2-10 mm, and preferably 6 mm. The outerdiameter of the transducer 30 is approximately 1.5-3 mm in diameter, andpreferably 2 mm. The physical structure of the transducer and itsmounting to the catheter may be, for example, as described in U.S. Pat.Nos. 7,540,846 and 6,763,722, the disclosures of which are incorporatedby reference herein. The transducer 30 also has conductive coatings (notshown) on its interior and exterior surfaces. Thus, the transducer maybe physically mounted on a metallic support tube 84 (FIG. 5), which inturn is mounted to the catheter. The coatings are electrically connectedto ground and signal wires 32. Wires 32 extend from the transducer 30through a lumen 34. The lumen 34 extends between the proximal end andthe distal end of a catheter 18, while the wires 32 extend from thetransducer 30, through the lumen 34, to the proximal end of the 14catheter 18.

Transducer 30 is arranged so that ultrasonic energy generated in thetransducer is emitted principally from the exterior emitting surface.Thus, the transducer may include features arranged to reflect ultrasonicenergy directed toward the interior of the transducer so that thereflected energy reinforces the ultrasonic vibrations at the exteriorsurface. For example, support tube 84 and transducer 30 may beconfigured so that the interior surface of the transducer 30 is spacedapart from the exterior surface of the support tube, which is formedfrom metal, by a gap (not shown). The distance across the gap, betweenthe interior surface of the transducer and the exterior surface of thesupport tube may be one half the wavelength of the ultrasound energyemitted by the transducer, to promote efficient operation of thetransducer 30. In this embodiment, the ultrasound energy generated bythe transducer 30 is reflected at the water gap to reinforce ultrasoundenergy propagating from the transducer 30, thereby ensuring theultrasound energy is directed outwardly from an external surface of thetransducer 30.

Transducer 30 is also arranged to convert ultrasonic waves impinging onthe exterior surface 31 into electrical signals on wires 32. Statedanother way, transducer 30 can act either as an ultrasonic emitter or anultrasonic receiver.

The transducer 30 is designed to operate, for example, at a frequency ofapproximately 1 MHz to approximately a few tens of MHz, and typically atapproximately 9 MHz. The actual frequency of the transducer 30 typicallyvaries somewhat depending on manufacturing tolerances. The optimumactuation frequency of the transducer may be encoded in amachine-readable or human-readable element (not shown) such as a digitalmemory, bar code or the like affixed to the catheter. Alternatively, thereadable element may encode a serial number or other informationidentifying the individual catheter, so that the optimum actuationfrequency may be retrieved from a central database accessible through acommunication link such as the internet.

An ultrasound system 20, also referred to herein as an actuator, isreleasably connected to catheter 18 and transducer 30 through a plugconnector 88 (FIG. 3). As seen in FIG. 6, ultrasound system 20 mayinclude a user interface 40, a control board 42 incorporating aprogrammable control device such as a programmable microprocessor (notshown), an ultrasound excitation source 44, and a circulation device 48.The user interface 40 interacts with the control board 42, whichinteracts with the excitation source 44 to cause transmission ofelectrical signals at the optimum actuation frequency of the transducerto the transducer 30 via wires 32. The control board 42 and ultrasoundsource 44 are arranged to control the amplitude and timing of theelectrical signals so as to control the power level and duration of theultrasound signals emitted by transducer 30. Excitation source 44 isalso arranged to detect electrical signals generated by transducer 30and appearing on wires 32 and communicate such signals to control board42.

The circulation device 48 is connected to lumens (not shown) withincatheter 18 which in turn are connected to balloon 24. The circulationdevice is arranged to circulate a liquid, preferably an aqueous liquid,through the catheter 18 to the transducer 30 in the balloon 24. Thecirculation device 48 may include elements such as a tank for holdingthe circulating coolant 35, pumps 37, a refrigerating coil (not shown),or the like for providing a supply of liquid to the interior space ofthe balloon 24 at a controlled temperature, desirably at or below bodytemperature. The control board 42 interfaces with the circulation device48 to control the flow of fluid into and out of the balloon 24. Forexample, the control board 42 may include motor control devices linkedto drive motors associated with pumps for controlling the speed ofoperation of the pumps 37. Such motor control devices can be used, forexample, where the pumps 37 are positive displacement pumps, such asperistaltic pumps. Alternatively or additionally, the control circuitmay include structures such as controllable valves connected in thefluid circuit for varying resistance of the circuit to fluid flow (notshown). The ultrasound system 20 may further include two pressuresensors 38, to monitor the liquid flow through the catheter 18. Onepressure sensor monitors the flow of the liquid to the distal catheter18 to determine if there is a blockage while the other monitors leaks inthe catheter 18. While the balloon is in an inflated state, the pressuresensors 38 maintain a desired pressure in the balloon preferably atapproximately 3 pounds per square inch (20 KPa).

The ultrasound system 20 incorporates a reader 46 for reading amachine-readable element on catheter 18 and conveying the informationfrom such element to control board 46. As discussed above, themachine-readable element on the catheter may include information such asthe operating frequency of the transducer 30 in a particular catheter18, and the control board 42 may use this information to set theappropriate frequency for exciting the transducer. Alternatively, thecontrol board may be arranged to actuate excitation source 44 to measurethe transducer operating frequency by energizing the transducer at a lowpower level while scanning the excitation frequency over apre-determined range of frequencies for example 8.5 Mhz-9.5 Mhz, andmonitoring the response of the transducer to such excitation.

The ultrasonic system 20 may be similar to that disclosed in U.S.Provisional Patent Application No. 61/256,002, filed Oct. 29, 2009,entitled “METHOD AND APPARATUS FOR PERCUTANEOUS TREATMENT OF MITRALVALVE REGURGITATION (PMVR),” the disclosure of which is incorporated byreference herein.

A method according to an embodiment of the present invention is depictedin flowchart form in FIG. 7. After preparing a human or non-humanmammalian subject such as a patient (step 50), preparation of anarterial access site such as a location on the femoral artery (step 52),and connecting the catheter 18 to the ultrasound system 20 (step 54),the ultrasound transducer 30 in inserted into the renal artery (step 56)by inserting the distal end of the sheath 12 through the access siteinto the aorta. While the distal end of the sheath is positioned withinthe aorta, the catheter 18 is advanced within the sheath until thedistal end of the catheter projects from the sheath as schematicallydepicted in FIG. 8. Because the distal end 22 of the catheter 18 ispre-formed like a hook, the distal end 22 of the catheter 18 may slideinto the renal artery 10 when the tip is rotated inside the aortatowards the renal artery 10 branches and then slightly pushed forwardand pulled backwards. This action is facilitated by the typical angle ofthe renal artery/aorta bifurcation. Based on the hooked shape of thedistal end 22, the distal end 22 of the catheter 18 may tend to catch inthe renal artery 10 side branch when pulled back inside the aorta. Theballoon 24 on the catheter desirably is maintained in a deflatedcondition until the distal end of the catheter is disposed at a desiredlocation within the renal artery. During insertion of the catheter 18and the transducer 30 (step 56), the physician may verify the placementof the transducer 30 to be within the renal artery 10, although beforethe kidney 6 or any branches of the renal artery 10 that may exist. Suchverification can be obtained using x-ray techniques such as fluoroscopy.

Once the distal end of the catheter is in position within a renalartery, pumps 37 bring balloon 24 to an inflated condition as depictedin FIGS. 4 and 5. In this condition, the non-circular portion 80 of theballoon engages the artery wall, and thus centers transducer 30 withinthe renal artery, with the axis 33 of the transducer (FIG. 5)approximately coaxial with the axis A of the renal artery. However, theballoon does not block blood flow through the renal artery. In thiscondition, the circulation device 48 maintains a flow of cooled aqueousliquid into and out of balloon 24, so as to cool the transducer 30. Thecooled balloon also tends to cool the interior surface of the renalartery. Moreover, the continued flow of blood through the renal arteryhelps to cool the interior surface of the renal artery. The liquidflowing within the balloon may include a radiographic contrast agent toaid in visualization of the balloon and verification of properplacement.

In the next step 58, the ultrasound system 20 uses transducer 30 tomeasure the size of the renal artery 10. Control board 42 and ultrasoundsource 44 actuate the transducer 30 to “ping” the renal artery 10 with alow-power ultrasound pulse. The ultrasonic waves in this pulse arereflected by the artery wall onto transducer 30 as echoes. Transducer 30converts the echoes to echo signals on wires 32. The ultrasound system20 then determines the size of the artery 10 by analyzing the echosignals. For example, the ultrasound system 20 may determine the timedelay between actuation of the transducer to produce the “ping” and thereturn of echo signals. In step 60, the ultrasound system 20 uses themeasured artery size to set the acoustic power to be delivered bytransducer 30 during application of therapeutic ultrasonic energy inlater steps. For example, control board 42 may use a lookup tablecorrelating a particular echo delay (and thus artery diameter) with aparticular power level. Generally, the larger the artery diameter, themore power should be used. Variations in the shape of the renal artery10, or in the centering of the transducer 30, may cause a range of timedelay in the echo signals. The ultrasound system 20 may take an averageof the range to determine the average size of the renal artery 10 andmake adjustments to the power level based on the average size.

The physician then initiates the treatment (step 60) through the userinterface 40. In the treatment (step 64), the ultrasonic system oractuator 20, and particularly the control board 42 and ultrasonic source44, actuate transducer 30 to deliver therapeutically effectiveultrasonic waves to an impact volume 11 (FIG. 5). The ultrasound energytransmitted by the transducer 30 propagates generally radially outwardlyand away from the transducer 30 encompassing a full circle, or 360° ofarc about the proximal-to-distal axis 33 of the transducer 30 and theaxis A of the renal artery.

The selected operating frequency, unfocused characteristic, placement,size, and the shape of the ultrasound transducer 30 allows the entirerenal artery 10 and renal nerves to lie within the “near field” regionof the transducer 30. Within this region, an outwardly spreading,unfocused omni-directional (360°) cylindrical beam of ultrasound wavesgenerated by the transducer 30 tends to remain collimated and has anaxial length approximately equal to the axial length of the transducer30. For a cylindrical transducer, the radial extent of the near fieldregion is defined by the expression L²/λ, where L is the axial length ofthe transducer 30 and λ is the wavelength of the ultrasound waves. Atdistances from the transducer 30 surface greater than L²/λ, the beambegins to spread axially to a substantial extent. However, for distancesless than L²/λ, the beam does not spread axially to any substantialextent. Therefore, within the near field region, at distances less thanL²/λ, the intensity of the ultrasound energy decreases linearly, inproportion to distance from the transducer 30 surface, as the unfocusedbeam spreads radially. As used in this disclosure, the term “unfocused”refers to a beam, which does not increase in intensity in the directionof propagation of the beam away from the transducer 30.

The impact volume 11 is generally cylindrical and coaxial with the renalartery. It extends from the transducer surface to an impact radius 39,where the intensity of the ultrasonic energy is too small to heat thetissue to the temperature range that will cause inactivation of therenal nerves 8. The impact radius 39 is determined by the dosage ofultrasound energy transmitted from the transducer 30. The volume V ofimpact volume 11 is determined by the following equation:

V=πr ₂ ² h−πr ₁ ² h

where

-   -   r₁=the radius of the transducer 30    -   r₂=the radius of the impact zone 11    -   h=length of the transducer 30

As discussed above, the length of the transducer 30 may vary between 2mm and 10 mm, but is preferably 6 mm to provide a wide inactivation zoneof the renal nerves. The diameter of the transducer 30 may vary between1.5 mm to 3.0 mm, and is preferably 2.0 mm. The dosage is selected notonly for its therapeutic effect, but also to allow the radius 39 of theimpact volume 11 to be between preferably 5 mm to 7 mm in order toencompass the renal artery 10, and adjacent renal nerves, all of whichlie within an average radius of 3-4 mm, without transmitting damagingultrasound energy to structures beyond the renal artery 10. This willresult in an impact volume 11 of at least 0.5 cm³, with the length ofrenal nerve inactivation closely corresponding to the length of thetransducer 32.

The power level desirably is selected so that throughout the impactvolume, solid tissues are heated to about 42° C. or more for at severalseconds or more, but desirably all of the solid tissues, including theintima of the renal artery remain well below 65° C. Thus, throughout theimpact region, the solid tissues (including all of the renal nerves) arebrought to a temperature sufficient to inactivate nerve conduction butbelow that which causes rapid necrosis of the tissues.

Research shows that nerve damage occurs at much lower temperatures andmuch faster than tissue necrosis. See Bunch, Jared. T. et al.“Mechanisms of Phrenic Nerve Injury During Radiofrequency Ablation atthe Pulmonary Vein Orifice, Journal of Cardiovascular Electrophysiology,Volume 16, Issue 12, pg. 1318-1325 (Dec. 8, 2005), incorporated byreference herein. Since, necrosis of tissue typically occurs attemperatures of 65° C. or higher for approximately 10 sec or longerwhile inactivation of the renal nerves 8 typically occurs when the renalnerves 8 are at temperatures of 42° C. or higher for several seconds orlonger, the dosage of the ultrasound energy is chosen to keep thetemperature in the impact volume 11 between those temperatures forseveral seconds or longer. The dosage of ultrasonic energy desirably isalso less than that required to cause substantial shrinkage of collagenin the impact volume. Operation of the transducer thus provides atherapeutic dosage, which inactivates the renal nerves 8 without causingdamage to the renal artery 10, such as, stenosis, intimal hyperplasia,intimal necrosis, or other injuries that would require intervention. Thecontinued flow of blood across the inside wall of the renal artery 10ensures the intimal layer 3 (FIG. 2) of the renal artery is cooled. Thisallows the ultrasound energy transmitted at the therapeutic dosage to bedissipated and converted to heat principally at the outer layers of therenal artery 10 and not at the intimal layer 3. In addition, thecirculation of cooled liquid through the balloon 24 containing thetransducer 30 may also help reduce the heat being transferred from thetransducer 30 to the intimal layer 3 and to the blood flowing past thetransducer. Hence, the transmitted therapeutic unfocused ultrasoundenergy does not damage the intima and does not provoke thrombusformation, providing a safer treatment.

In order to generate the therapeutic dosage of ultrasound energy, theacoustic power output of the transducer typically is approximately 10watts to approximately 100 watts, more typically approximately 20 toapproximately 30 watts. The duration of power application typically isapproximately 2 seconds to approximately a minute or more, moretypically approximately 10 seconds to approximately 20 seconds. Theoptimum dosage used with a particular system to achieve the desiredtemperature levels may be determined by mathematical modeling or animaltesting.

The impact volume 11 of the unfocused ultrasound energy encompasses theentire renal artery 10, including the adventitia and closely surroundingtissues, and hence encompasses all of the renal nerves surrounding therenal artery. Therefore, the placement in the renal artery 10 of thetransducer 30 may be indiscriminate in order to inactivate conduction ofall the renal nerves 8 surrounding the renal arteries 10 in the subject.As used in this disclosure “indiscriminate” and “indiscriminately” meanwithout targeting, locating, or focusing on any specific renal nerves.

Optionally, the physician may then reposition the catheter 18 andtransducer 30 along the renal artery (step 66) and reinitiate thetreatment 68 to retransmit therapeutically effective unfocusedultrasound energy (step 70). This inactivates the renal nerves at anadditional location along the length of the renal artery, and thusprovides a safer and more reliable treatment. The repositioning andretransmission steps optionally can be performed multiple times. Nextthe physician moves the catheter 18 with the transducer 30 to the otherrenal artery 10 and performs the entire treatment again for that artery10, (step 72). After completion of the treatment, the catheter 18 iswithdrawn from the subject's body (step 74).

Numerous variations and combinations of the features discussed above canbe utilized. For example, the ultrasound system 20 may control thetransducer 30 to transmit ultrasound energy in a pulsed function duringapplication of therapeutic ultrasonic energy. The pulsed function causesthe ultrasound transducer 30 to emit the ultrasound energy at a dutycycle of, for example, 50%. Pulse modulation of the ultrasound energy ishelpful in limiting the tissue temperature while increasing treatmenttimes.

In a further variant, the steps of measuring the renal artery size andadjusting the dose (steps 58 and 72) may be omitted. In this instance,the transducer is simply operated at a preset power level sufficient forthe renal arteries of an average subject. In a further variant, therenal artery diameter can be measured by techniques other than actuationof transducer 30 as, for example, by radiographic imaging using acontrast agent introduced into the renal artery or magnetic resonanceimaging or use of a separate ultrasonic measuring catheter. In thisinstance, the data from the separate measurement can be used to set thedose.

In the particular embodiment discussed above, the transducer 30 iscentered in the renal artery by the non-circular element 80 ofexpansible balloon 24. Other centering arrangements can be used. Forexample, an expansible balloon encompassing the transducer may be aballoon of circular cross-section slightly smaller in diameter than therenal artery 10. Such a balloon allows blood to continue to flow throughthe renal artery 10, but maintains the transducer 30 roughly centered inthe renal artery 10. In this embodiment, the balloon 24 is dynamicrather than fitted to the renal artery 10 because the flow of bloodaround the balloon 24 causes small back and forth movements. Thisdynamic nature allows the blood to continue to reach all parts of therenal artery 10, thereby providing cooling and minimizing damage to theintima 3. In other embodiments, the distal end of the catheter caninclude expansible structures other than balloons, such as a wire basketor wire mesh structure which can be selectively brought to a radiallyexpanded condition, such as by compressing the structure in the axialdirection. The wire basket may be non-reflecting to ultrasound, or maybe mounted on the catheter at a position axially offset from thetransducer 30.

In a further variant, the balloon 24 may be formed from a porousmembrane or include holes, such that cooled liquid being circulatedwithin the balloon 24 may escape or be ejected from the balloon 24 intothe blood stream within the renal artery 10. The escaping or ejectedcooled liquid from the balloon 24 that enters the blood flow may supportfurther cooling of the inner lining of the renal artery 10, which is incontact with the flowing blood.

Typically, catheter 18 is a disposable, single-use device. The catheter18 or ultrasonic system 20 may contain a safety device that inhibits thereuse of the catheter 18 after a single use. Such safety devices per seare known in the art.

In yet another variant, the catheter 18 itself may include a steeringmechanism which allows the physician to directly steer the distal end 22of the catheter. The sheath may be omitted.

Another variation may be that an energy emitter unit at the distal endof the catheter 18, which includes the ultrasound transducer 30, may bepositioned in the renal vein, and the ultrasound transducer 30 mayinclude reflective or blocking structures for selectively directingultrasound energy from the transducer 30 over only a limited range ofradial directions to provide that ultrasound energy desirably isselectively directed from the transducer 30 in the renal vein toward therenal artery 10. When the venous approach is utilized, the ultrasoundenergy is directed into a segment or beam propagating away from anexterior surface of the transducer 30, commonly known as a side firingtransducer 30 arrangement. For example, the ultrasound transducer 30 mayhave a construction and be operated to emit directed ultrasound energy 5similarly as disclosed in US Provisional Application No. 61/256,002,filed Oct. 29, 2009, entitled “METHOD AND APPARATUS FOR PERCUTANEOUSTREATMENT OF MITRAL VALVE REGURGITATION (PMVR),” incorporated byreference herein. In this variation, the route by which the catheter 18is introduced into the body, and then positioned close to the kidneys 6,is varied from the atrial approach discussed above. A venous approachmay be utilized to take advantage of the potential for reduced closureissues after catheter 18 withdrawal.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

1. Apparatus for inactivating renal nerve conduction in a mammaliansubject comprising: an ultrasound transducer adapted for insertion intoa renal artery of the mammalian subject and for transmitting unfocusedultrasound energy; and an actuator electrically connected to thetransducer, the actuator being adapted to control the ultrasoundtransducer to transmit unfocused ultrasound energy into an impact volumeof at least 0.5 cm³, encompassing the renal artery so that the unfocusedultrasound energy is applied at a therapeutic level sufficient toinactivate conduction of renal nerves throughout the impact volume. 2.The apparatus of claim 1, wherein the actuator is adapted to control theultrasound transducer so that the unfocused ultrasound is appliedthroughout the impact volume at a level insufficient to cause rapidnecrosis of tissues.
 3. The apparatus of claim 2, wherein the impactvolume encompasses all of the renal nerves surrounding the renal artery.4. The apparatus of claim 1, wherein the actuator is adapted to controlthe ultrasound transducer to transmit unfocused ultrasound energy at anacoustic power level of 10 to 30 watts for 10 to 30 seconds to providean absorbed dose of 100 to 900 joules in the impact volume.
 5. Theapparatus of claim 1, wherein the actuator is adapted to control thetransducer so as to maintain the temperature of the renal artery wallbelow 65° C. while achieving a temperature above 42° C. throughout theimpact volume for several seconds or more.
 6. The apparatus of claim 1,wherein the actuator is adapted to control the ultrasound transducer totransmit the unfocused ultrasound energy in a pulsed function.
 7. Theapparatus of claim 1, wherein the ultrasound transducer is adapted totransmit the ultrasound energy in a pattern having a length of at leastapproximately 2 mm along the axis of the renal artery.
 8. The apparatusof claim 1, wherein the transducer is adapted to apply the ultrasonicenergy at the therapeutic level throughout an impact volume having alength of at least approximately 2 mm along the axis of the of the renalartery.
 9. The apparatus of claim 5, further comprising a catheter witha distal end and a proximal end, the transducer being mounted to thecatheter adjacent the distal end, the catheter and transducer beingconstructed and arranged to allow a substantial flow of blood throughthe renal artery while the ultrasound transducer is positioned withinthe renal artery.
 10. The apparatus of claim 9, wherein the catheter isconstructed and arranged to hold the transducer out of contact with thewall of the renal artery.
 11. The apparatus of claim 9, wherein thetransducer has an axis, the catheter is constructed and arranged to holdthe axis of the transducer generally parallel to the axis of the renalartery, and the transducer is adapted to transmit the ultrasound energyin a 360° cylindrical pattern surrounding the axis of the transducer.12. The apparatus of claim 10, wherein the catheter includes a centeringelement in proximity to the transducer, the centering element beingarranged to hold the transducer substantially centered in the renalartery.
 13. The apparatus of claim 12, wherein the centering elementincludes an expansible element adapted to engage the wall of the renalartery without substantially blocking flow of blood through the renalartery.
 14. The apparatus of claim 1, wherein the ultrasound transduceris further adapted to receive ultrasound energy and generate signalsrepresenting the received ultrasonic energy and the actuator is furtheradapted to: control the ultrasound transducer to transmit measurementultrasound energy at a level below the therapeutic level, receive echosignals from the transducer representing reflected measurementultrasonic energy; analyze the received echo signals; and determine asize of the renal artery based on the received echo signal.
 15. Theapparatus of claim 14, wherein the ultrasound system is adapted tocontrol the ultrasound transducer to vary the acoustic power used totransmit the therapeutically effective unfocused ultrasound energydepending on the determined size of the renal artery.
 16. A method forinactivating renal nerve conduction in a mammalian subject comprisingthe steps of: inserting an ultrasound transducer into a renal artery ofthe mammalian subject; and actuating the transducer to transmit apredetermined therapeutically effective dose of unfocused ultrasoundenergy into an impact volume of at least approximately 0.5 cm³,encompassing the renal artery so that the therapeutically effective doseof unfocused ultrasound energy inactivates conduction of all the renalnerves in the impact volume.
 17. The method of claim 16, wherein theultrasound energy is transmitted at an acoustic power level ofapproximately 10 to approximately 30 watts for approximately 10 toapproximately 30 seconds to provide an absorbed dose of approximately100 to approximately 900 joules throughout the impact volume.
 18. Themethod of claim 16, wherein the step of transmitting ultrasound energyis performed so as to maintain the temperature of the renal artery wallbelow 65° C. while heating the renal nerves in the impact region toabove 42° C.
 19. The method of claim 16, wherein the steps of insertingthe ultrasound transducer and actuating the transducer to transmitultrasound energy are performed without determining the actual locationsof renal nerves.
 20. The method of claim 16, wherein the step ofactuating the transducer is performed so that a single application ofthe ultrasound energy in each renal artery is effective to inactivateconduction of all the renal nerves surrounding that renal artery. 21.The method of claim 16, further comprising the steps of: repositioningthe ultrasound transducer in the renal artery after the step ofactuating the transducer; and then repeating the step of actuating thetransducer.
 22. The method of claim 16, wherein the step of actuatingthe transducer is performed so that the ultrasound energy is transmittedin a pulsed function.
 23. The method of claim 16, wherein the step ofinserting the ultrasound transducer is performed so as to permit asubstantial flow of blood through the renal artery while the transduceris positioned within the renal artery.
 24. The method of claim 16,wherein the step of inserting the ultrasound transducer into the renalartery is performed so that the transducer does not contact the wall ofthe renal artery.
 25. The method of claim 16, wherein thetherapeutically effective unfocused ultrasound energy is transmitted ina 360° cylindrical pattern surrounding the transducer.
 26. The method ofclaim 16, wherein the therapeutically effective unfocused ultrasoundenergy is transmitted in a pattern having a length of at leastapproximately 2 mm along the axis of the renal artery.
 27. The method ofclaim 16, wherein the therapeutically effective unfocused ultrasoundenergy inactivates conduction of a length of at least approximately 2 mmof the renal nerves.
 28. The method of claim 16, further comprising thestep of substantially centering the ultrasound transducer in the renalartery prior to the step of transmitting the therapeutically effectiveunfocused ultrasound energy.
 29. The method of claim 27, wherein thestep of substantially centering the transducer is performed so as toallow a substantially undiminished flow of blood through the renalartery.
 30. The method of claim 16, further comprising the steps of:applying non-therapeutic ultrasound energy at a power level less than apower level of the therapeutically effective ultrasonic energy;receiving reflected non-therapeutic ultrasonic energy and generatingecho signals representing the reflected energy; and determining a sizeof the renal artery based on the echo signals before the step ofactuating the transducer to apply the therapeutically effectiveultrasonic energy.
 31. The method of claim 30, further comprising thestep of adjusting the power applied to the transducer during actuationto emit therapeutically effective unfocused ultrasound energy based atleast in part on the size of the renal artery determined in thedetermining step.
 32. A probe for use in renal nerve inactivation, theprobe comprising: an ultrasound transducer adapted for transmittingunfocused ultrasound energy; and a catheter with a distal end and aproximal end, the transducer being mounted to the catheter adjacent thedistal end, the catheter and transducer being constructed and arrangedto allow positioning of the distal end and transducer within a renalartery and to allow a substantial flow of blood through the renal arterywhile the ultrasound transducer is positioned within the renal artery.33. The probe of claim 32, wherein the catheter is constructed andarranged to hold the transducer out of contact with the wall of therenal artery.
 34. The probe of claim 32, wherein the transducer has anaxis, the catheter is constructed and arranged to hold the axis of thetransducer generally parallel to the axis of the renal artery, and thetransducer is adapted to transmit the ultrasound energy in a 360°cylindrical pattern surrounding the axis of the transducer.
 35. Theprobe of claim 32, wherein the catheter includes a centering element inproximity to the transducer, the centering element being arranged tohold the transducer substantially centered in the renal artery.
 36. Theprobe of claim 35, wherein the centering element includes an expansibleelement adapted to engage the wall of the renal artery withoutsubstantially blocking flow of blood through the renal artery.
 37. Theprobe of claim 32 further comprising an inflatable balloon surroundingthe transducer, the balloon having a non-circular portion which, in aninflated condition, has a major diameter adapted to contact the wall ofthe renal artery and has a minor diameter smaller than the diameter ofthe renal artery, the catheter having fluid lumens communicating withthe balloon, the probe further comprising a circulation devicecommunicating with the balloon through the lumens for circulating aliquid through the balloon.
 38. Apparatus for inactivating renal nerveconduction in a mammalian subject comprising: an ultrasound transducer;means for positioning the ultrasound transducer in a renal artery of themammalian subject so that said transducer is spaced all around from awall of said artery; and means for actuating the transducer to transmita predetermined therapeutically effective dose of unfocused ultrasoundenergy into an impact volume of at least 0.5 cm³, encompassing the renalartery and achieves a temperature above 42° C. throughout the impactvolume for several seconds or more while maintaining the temperature ofthe renal artery wall below 65° C. so that the therapeutically effectivedose of unfocused ultrasound energy inactivates conduction of all therenal nerves which are disposed in the impact volume without damagingthe intima of the renal artery.
 39. An apparatus for inactivating renalnerves comprising: an ultrasound transducer adapted to emit unfocusedultrasound energy radially outwardly at a frequency transmittablethrough the renal artery to the renal nerves, the ultrasound transducerhaving: a shape suitable to produce unfocused ultrasound energy with alength of at least 2 mm, an axial length suitable for insertion into therenal artery, and a diameter suitable to allow fluid to flow around thetransducer while the transducer is inserted in the renal artery, thefluid providing cooling to the renal artery; and an actuatorelectrically connected to the transducer, the actuator adapted tocontrol the ultrasound transducer to transmit the unfocused ultrasoundenergy at a power level and duration that generates: a near field regionof ultrasound energy that encompasses the renal artery, and atherapeutic ultrasound energy level in the near field region that issufficient to inactivate the renal nerves.
 40. The apparatus of claim39, wherein the actuator is adapted to control the ultrasound transducerto transmit unfocused ultrasound energy at a frequency of 5 MHz to 15MHz.
 41. The apparatus of claim 39, wherein the shape of the transduceris cylindrical and transmits the unfocused ultrasound energy in a 360°cylindrical pattern.
 42. The apparatus of claim 39, wherein the nearfield region does not encompass other structures of the body.
 43. Theapparatus of claim 39, wherein the fluid providing cooling to the renalartery is a continuous flow of blood through the renal artery.
 44. Theapparatus of claim 39, further comprising: a catheter with a distal endand a proximal end, the ultrasound transducer mounted to the catheteradjacent the distal end; an expansible element mounted to the catheterin proximity to the ultrasound transducer.
 45. The apparatus of claim44, wherein the expansible element contains cooling fluid to cool thetransducer and the renal artery.
 46. The apparatus of claim 44, whereinthe expansible element is shaped to allow a continuous flow of blood tocool the renal artery.
 47. The apparatus of claim 44, wherein theexpansible element is a centering element.
 48. The apparatus of claim39, wherein the power level is an acoustic power level of 10 to 30 wattsand the duration is 10 to 30 seconds to provide an absorbed dose of 100to 900 joules in the near field region.
 49. The apparatus of claim 39,wherein the therapeutic ultrasound energy level maintains thetemperature of the renal artery wall below 65° C. while achieving atemperature above 42° C. throughout the near field region for severalseconds or more.
 50. The apparatus of claim 39, wherein the unfocusedultrasound is applied throughout the near field region at a levelinsufficient to cause rapid necrosis of tissues.
 51. The apparatus ofclaim 39, wherein the near field region encompasses all of the renalnerves surrounding the renal artery.
 52. An apparatus for deactivatingrenal nerves to treat hypertension, comprising: an ultrasound transducerdevice configured to generate a volumetric distribution of ultrasoundradiation where intensity of an ultrasound field decreases with distancefrom the transducer device, said transducer device being so dimensionedas to enable insertion and disposition thereof inside a renal artery; asupport element operatively connected to said transducer device, saidsupport element being configured to support said transducer device sothat said transducer device is not in contact with renal artery tissue;and a control unit operatively connected to said transducer device forenergizing same with an ultrasonic electrical signal with frequency,amplitude, and duration parameters selected so that said volumetricdistribution of ultrasound radiation encompasses the renal artery andhas a therapeutic ultrasound energy level that is sufficient toinactivate renal nerves within said volumetric distribution ofultrasound radiation.
 53. The apparatus of claim 52 wherein saidultrasound transducer device has a length of about 2 mm and saidvolumetric distribution of ultrasound radiation has a length of about 2mm.
 54. The apparatus of claim 52 wherein said ultrasound transducerdevice is configured to generate a cylindrical distribution ofultrasound radiation.
 55. The apparatus of claim 52 wherein said supportelement is a centering element allowing for blood flow through the renalartery and past said transducer.
 56. The apparatus of claim 52 whereinsaid volumetric distribution of ultrasound radiation encompasses allrenal nerves within a predetermined distance of said transducer device.57. A method for deactivating renal nerves to treat hypertension,comprising: inserting an ultrasound transducer into a renal artery;feeding an electrical signal of ultrasonic frequency to said transducer;and in response to the feeding of said electrical signal, energizingsaid transducer to generate a volumetric ultrasound field that decreasesin intensity with distance from said transducer and that encompasses along segment of said renal artery, including renal nerves dispersedcircumferentially and longitudinally along said renal artery, whereinsaid electrical signal has frequency, amplitude, and duration parametersselected to produce a therapeutic ultrasound energy level within saidvolumetric ultrasound field sufficient to inactivate renal nervesthroughout said volumetric ultrasound field.
 58. The method of claim 57wherein said volumetric ultrasound field is axially symmetric about saidtransducer.
 59. The method of claim 58, further comprising positioningsaid transducer within the renal artery so that said transducer is notin contact with arterial tissue.